title: Mitogen-activated protein kinase phosphatase 1 disrupts proinflammatory protein synthesis in endotoxin-adapted monocytes.
abstract: Autotoxic production of proinflammatory mediators during early sepsis induces excessive inflammation, and their later suppression may limit the immune response. We previously reported that sepsis differentially represses transcription and translation of tumor necrosis factor alpha (TNF-α) and interleukin 1β (IL-1β) to reprogram sepsis inflammation. This switch is gene specific and plays a crucial role in the clinically relevant syndrome of endotoxin adaptation/tolerance, multiorgan failure, and poor sepsis outcome. To further define the mechanisms responsible for translation disruption that follows inflammation induction, we used THP-1 human promonocytes as a model of Toll-like receptor 4 (TLR4) responses found in sepsis. We showed that phosphorylation-dependent activation of p38 mitogen-activated protein kinase (MAPK) and translation disruption of TNF-α and IL-6 follow increased MAPK phosphatase 1 (MKP-1) expression and that MKP-1 knockdown rephosphorylates p38 and restores the capacity to translate TNF-α and IL-6 mRNAs. We also observed that the RNA-binding protein motif 4 (RBM4), a p38 MAPK target, accumulates in an unphosphorylated form in the cytosol in endotoxin-adapted cells, suggesting that dephosphorylated RBM4 may function as a translational repressor. Moreover, MKP-1 knockdown promotes RBM4 phosphorylation, blocks its transfer from the nucleus to the cytosol, and reverses translation repression. We also found that microRNA 146a (miR-146a) knockdown prevents and miR-146a transfection induces MKP-1 expression, which lead to increases or decreases in TNF-α and IL-6 translation, respectively. We conclude that a TLR4-, miR-146a-, p38 MAPK-, and MKP-1-dependent autoregulatory pathway regulates the translation of proinflammatory genes during the acute inflammatory response by spatially and temporally modifying the phosphorylation state of RBM4 translational repressor protein.
authors.affiliation: Departments of Internal Medicine, East Tennessee State University College of Medicine, Johnson City, Tennessee, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Brudecki
authors.forename: Donald A
authors.initials: DA
authors.lastname: Ferguson
authors.forename: Charles E
authors.initials: CE
authors.lastname: McCall
authors.forename: Mohamed
authors.initials: M
authors.lastname: El Gazzar
mesh_terms: D002460:Cell Line; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism*; D004731:Endotoxins / Q000276:immunology*; D055785:Gene Knockdown Techniques; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis; D035683:MicroRNAs / Q000378:metabolism; D009000:Monocytes / Q000276:immunology*; D014176:Protein Biosynthesis; D016601:RNA-Binding Proteins / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D004731:Endotoxins; D015850:Interleukin-6; C542542:MIRN146 microRNA, human; D035683:MicroRNAs; C473692:RBM4 protein, human; D016601:RNA-Binding Proteins; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1